Targeting ERBB2 mutations in urothelial carcinoma.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 354-354
Author(s):  
Francois Audenet ◽  
Sumit Isharwal ◽  
Maria E. Arcila ◽  
Samuel Funt ◽  
Jonathan E. Rosenberg ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Allele Frequency ◽  
Kinase Inhibitors ◽  
Hot Spot ◽  
Genetic Alterations ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Stage Disease ◽  
Muscle Invasive

354 Background: ERBB2 encodes human epidermal growth factor receptor 2 (HER2), a member of the EGFR family of receptor tyrosine kinases that signal through the pro-oncogenic MAP- and PI3K-kinase pathways. ERBB2 is altered by amplification and/or overexpression in various cancers, including urothelial carcinoma (UC). These alterations could confer sensitivity to ERBB2 kinase inhibitors in selected patients with UC. Methods: Patients diagnosed with UC were enrolled onto an institutional review board approved prospective sequencing protocol. Tumor and matched germline DNA were analyzed using the MSK-IMPACT assay that detects alterations in 410 oncogenes and tumor suppressor genes, including ERBB2. Results: Overall, 449 samples from 429 patients were sequenced from 2013 to August 2016. Genetic alterations in ERBB2 were found in 78 samples (17%). At the time of sample collection, 24 patients (31%) had non-muscle invasive bladder cancer (NMIBC), 30 patients (38%) had muscle-invasive bladder cancer (MIBC), 18 (23%) had metastatic disease and 7 (8%) had upper tract urothelial carcinoma (UTUC). Sixteen samples (21%) came from metastatic specimens. Of the observed 78 ERBB2 alterations, 20 samples had amplifications (26%) and 58 samples had mutations (74%). Seven samples (9%) had both. We identified 71 missense, 2 inframe and 1 fusion alteration, corresponding to a somatic mutation rate of 13.1%. Thirty-seven mutations (50%) were functionally characterized hot spots that are potentially actionable. Of note, the hot spot mutation S310F/Y was found in 29 samples (37%). Its mutation allele frequency varied significantly. There was a trend towards a higher mutant allele frequency of S310F/Y in higher stage disease without reaching statistical significance (Table). In our cohort, 3 patients were enrolled in clinical trials with ERBB2 kinase inhibitors based upon the presence of an ERBB2alteration. Conclusions: ERBB2is a frequent mutation at different stages of UC. In higher stage disease, clonal selection of the S310F/Y hot-spot mutation may occur and requires further study. [Table: see text]

scholarly journals Elucidation of Novel Molecular Targets for Therapeutic Strategies in Urothelial Carcinoma: A Literature Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Blessie Elizabeth Nelson ◽  
Angelina Hong ◽  
Bagi Jana
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Urothelial Cancer ◽  
Kinase Inhibitors ◽  
Therapeutic Agents ◽  
Invasive Bladder Cancer ◽  
Treatment Modalities ◽  
Muscle Invasive Bladder Cancer ◽  
T Cell Therapy ◽  
Muscle Invasive

Urothelial carcinoma therapy is a rapidly evolving and expanding field. Traditional cytotoxic chemotherapy regimens have not produced optimal long-term outcomes, and many urothelial cancer patients have comorbidities that disqualify them as chemotherapy candidates. In recent years, a plethora of novel therapeutic agents that target diverse molecular pathways has emerged as alternative treatment modalities for not only metastatic urothelial carcinoma, but also for muscle-invasive bladder cancer and non-muscle invasive bladder cancer in adjuvant and definitive settings. This review paper aims to discuss the various categories of therapeutic agents for these different types of urothelial cancer, discussing immunotherapy, antibody-drug conjugates, kinase inhibitors, CAR-T cell therapy, peptide vaccination, and other drugs targeting pathways such as angiogenesis, DNA synthesis, mTOR/PI3K/AKT, and EGFR/HER-2.

The impact of histologic variants of urothelial carcinoma on clinical outcomes following trimodal bladder-preserving therapy.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 421-421
Author(s):  
Yoshiyuki Nagumo ◽  
Shuya Kandori ◽  
Tomokazu Kimura ◽  
Takashi Kawahara ◽  
Takahiro Kojima ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Clinical Outcomes ◽  
Invasive Bladder Cancer ◽  
Rank Test ◽  
Muscle Invasive Bladder Cancer ◽  
Bladder Preservation ◽  
Significant Difference ◽  
Muscle Invasive ◽  
The Impact

421 Background: The current guidelines for muscle-invasive bladder cancer recommend the use of neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. However, a trimodal approach involving the combination of maximal transurethral resection (TUR) and combined chemoradiotherapy is an alternative in selected patients. Clinical outcomes of patients with histologic variants have not well been known. Methods: From 1990 to 2015, 148 patients with cT2-3N0M0 muscle-invasive bladder cancer underwent trimodal bladder-preserving therapy consisting of maximal TUR of the bladder tumor, intra-arterial chemotherapy and radiotherapy at our institution. We compared complete response rate (CRR) of bladder preservation, 5-yr cause-specific survival (CSS), and 5-yr overall survival (OS) for the patients with pure urothelial carcinoma (UC) or variant UC. OS and CSS were analyzed by using the Kaplan-Meier method and log-rank test. Results: The median follow-up was 38.3 months. All patients were T2-T3N0M0 (T2, n = 90; T3, n = 58). There were no significant differences in clinical characteristics between pure and variant UC groups. Eleven (7%) of the 148 patients had variant UC; 7 (64%) had UC with squamous and/or glandular differentiation, and 4 (36%) had other forms, including sarcomatoid (n = 1), plasmacytoid (n = 1), signet ring cell (n = 1), and clear cell variants (n = 1). There was no significant difference between pure UC and variant UC for CRR of bladder preservation (85% vs 82%, p = 0.66), the 5-yr CSS (88% vs 75%, p = 0.86) and the 5-yr OS (81% vs 75%, p = 0.66). Conclusions: Our findings indicate that trimodal bladder-preserving therapy can be an effective treatment option for selected muscle-invasive bladder cancer patients with variant UC.

scholarly journals Complications of radical cystectomy for bladder cancer

2018 ◽  
Vol 6 (12) ◽  
pp. 3898
Author(s):  
Maliikarjuna Gurram ◽  
Ravichander G. ◽  
Ravi Jahagidar ◽  
Vinay Reddy
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Radical Cystectomy ◽  
Bladder Tumor ◽  
Invasive Bladder Cancer ◽  
Safe Procedure ◽  
High Grade ◽  
Early Complications ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

Background: Radical cystectomy with pelvic lymph node dissection is the standard treatment for muscle-invasive bladder cancer. With the advent of improved surgical techniques and postoperative management, the complications and mortality rates have reduced. The present study was done to analyse the perioperative, early and late compilations following radical cystectomy for bladder tumor.Methods: This is a prospective observational study of patients who underwent radical cystectomy for invasive bladder tumor from February 2016 to November 2017. Radical cystectomy was done through midline transperitoneal approach.  Urinary diversion was done by ileal conduit. All patients were followed at 6th week, 3rd month, 6th month, and at 1 year.Results: Total 21 patients underwent radical cystectomy, 17(80.95%) were males and 4 (19.04%) females. The median age was 60 years, ranging from 40 to 73 years. The   most common age group was 60 to 75 years (52.3%). Thirteen (61.9%) patients were smokers and all were males. Painless haematuria alone was most common presentation (of bladder tumor) seen in 15 (71.4%) patients. Early complications were seen in 8 (38.09%) patients, most common early complication was urinary leak 2 (9.5%) patents, other early complications were bowel leak, wound dehiscence, pelvic collection, burst abdomen, prolonged ileus, subacute intestinal obstruction, acute kidney injury and sepsis seen in one (4.25%) patient each. Late complications were seen in 4 (19.04%) patients.  Pelvic recurrence was the most common late complication seen in 2 (9.55%) patients. Ureteric stricture was seen in one patient (4.75%) for which percutaneous nephrostomy and antegrade DJ stenting was done. Among the histopathological variants of tumor 20 (95.25%) patients had high grade variants and only one (4.75%) had low grade papillary urothelial carcinoma. Among the high grade variants most common pathology was urothelial carcinoma in 17 (80.9%) patients.Conclusions: Radical cystectomy remains the main stay of treatment in muscle-invasive bladder cancer. This is relatively safe procedure with minimal morbidity and mortality.

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